Discovery of lipid peroxidation products formed in vivo with a substituted tetrahydrofuran ring (isofurans) that are favored by increased oxygen tension

Abstract

Free radicals have been implicated in the pathogenesis of an increasing number of diseases. Lipids, which undergo peroxidation, are major targets of free radical attack. We report the discovery of a pathway of lipid peroxidation that forms a series of isomers in vivo that are characterized by a substituted tetrahydrofuran ring structure, termed isofurans (IsoFs). We have proposed two distinct pathways by which IsoFs can be formed based on 18 O2 and H2 18 O labeling studies. Measurement of F2-isoprostanes (IsoPs), prostaglandin F2-like compounds formed nonenzymatically as products of lipid peroxidation, is considered one of the most reliable approaches for assessing oxidative stress status in vivo. However, one limitation with this approach is that the formation of IsoPs becomes limited at high oxygen tension. In contrast, the formation of IsoFs becomes increasingly favored as oxygen tension increases. IsoFs are present at readily detectable levels in normal fluids and tissues, and levels increase dramatically in CCl 4-treated rats, an animal model of oxidant injury. The ratio of IsoFs to IsoPs in major organs varies according to normal steady-state tissue oxygenation. In addition, IsoFs show a marked increase early in the course of hyperoxia-induced lung injury, whereas IsoPs do not significantly increase. We propose that combined measurement of IsoFs and IsoPs should provide a more reliable index of oxidant stress severity than quantification of either alone because of the opposing modulation of the two pathways by oxygen tension, which can vary widely in different organs and disease states.

Oxidized Low-Density Lipoprotein Is Present in Astrocytes Surrounding Cerebral Infarcts and Stimulates Astrocyte Interleukin-6 Secretion

“…IsoFs are recently described products of the same pathway whose formation is favored over IsoPs under conditions of increased oxygen tension, such as cell culture experiments and ex vivo oxidation, as occurred in the experiments described here. 21 LDL oxidation displayed the expected sequence of well-described changes. 26 DiIoxLDL was oxidized under three different conditions that yielded increasingly damaged LDL, as evidenced by consumption of ␣-tocopherol, increase in F 2 -IsoPs and IsoFs, and degradation of apoB immunoreactivity.…”

“…20,21 Samples were homogenized using a Brinkmann polytron motorized tissue grinder, and lipids were extracted using the Folch method (chloroform:methanol 2:1 v/v) supplemented with 0.005% (w/v) butylated hydroxytoluene to prevent auto-oxidation. After evaporation to dryness under nitrogen, lipids were hydrolyzed with 15% (w/v) potassium hydroxide to release esterified F 2 -IsoPs and IsoFs, and the internal standard [ 2 H 4 ]15-F 2t -IsoP added to the samples.…”

Identification of a Novel Class of Endoperoxides from Arachidonate Autoxidation

“…Bicyclic endoperoxides (1a), monocyclic peroxides (1b), and serial cyclic peroxides (1c) have previously been characterized from the mixture of products formed in the autoxidation of cholesteryl arachidonate (8,12,13). Oxidation products having a tetrahydrofuran moiety (1d) were recently characterized under conditions of reaction having increased oxygen tension (14). The epoxyisoprostanes (1e) and epoxycyclopentenones (1f) are probably derived from the bicyclic endoperoxides (15,16).…”

Isofurans, but not F2‐isoprostanes, are increased in the substantia nigra of patients with Parkinson's disease and with dementia with Lewy body disease

“…Given the existing evidence of oxidative damage in PD, F 2 -IsoPs would be expected to increase in the SN of PD patients. However, the recent discovery of a novel series of lipid peroxidation products that contain a substituted tetrahydrofuran ring, termed isofurans (IsoFs), has shed light on a potential limitation of using F 2 -IsoPs as an index of oxidant injury in settings of elevated oxygen tension (Fessel et al 2002). IsoF formation is increasingly favored with increasing oxygen tension in vitro and in vivo.…”